The goal of this proposal is to define the genetic basis of ankylosing spondylitis (AS) susceptibility. This[unreadable] project is centered around four hypotheses; 1) that the MHC contribution to the genetic basis of AS, though[unreadable] primarily provided by HLA-B27, is augmented by other MHC influences that require novel approaches to[unreadable] elucidate; 2) that the contribution of non-MHC genes, though vital, is sufficiently small to require large[unreadable] sample sizes and confirmation in independent cohorts; 3) that these genetic factors interact with each other[unreadable] in a complex manner to influence disease susceptibility; and 4) that rigid and consistent phenotypic[unreadable] characterization is crucial to the success of any genetic study, particularly that of AS. The specific aims of[unreadable] this project are, therefore: 1. To establish a resource of U.S. AS cases and locale matched controls for[unreadable] genemapping studies by increasing our resource of cases and controls up to a total of 1500 of each. 2. To[unreadable] perform a genomewide scan of susceptibility to AS in 1000 British patients meeting modified New York[unreadable] criteria for AS, and 3000 Controls. We will examine 675,000 SNP's using the 500K Affymetrix chip and a[unreadable] 175K SNP chip from Perlegen in a group of 1,000 U.K. patients meeting the modified New York criteria for[unreadable] A.S. compared with 3,000 U.K. controls for all the SNPs under consideration. 3. To confirm initial positive[unreadable] findings fof the most significant 1.4% of the SNPs from the genomewide association study in 1500 U.S. AS[unreadable] cases and locale matched controls. 4. To investigate the role of gene-gene interaction in AS-susceptibility.[unreadable] This will be the largest and most comprehensive study of the genetic basis of AS susceptibility undertaken to[unreadable] date, and has a high likelihood of greatly increasing the proportion of the heritability of AS-susceptibility for[unreadable] which genes have been identified. By encompassing the two largest cohorts of AS patients examined to[unreadable] date, utilizing cutting edge technologies and analystic approaches, and careful phenotyping, we believe that[unreadable] his study will produces major advances inour understanding of the genetic basis of AS.